Protein translation and ER stress in intestinal homeostasis and cancer

This thesis explores the interaction between protein translation control mechanisms and colon cancer.
We first investigate translation potential of cancer cells by implementing consecutive oncogenic mutations in intestinal organoids. We find increased global translation capacity following accumulation of mutations. We additionally demonstrate, by chemically inhibiting translation initiation, growth of organoids with multiple oncogenic mutations can be restrained.
Previous work has shown that activation of the Unfolded Protein Response, a major translational quality control mechanism, results in differentiation of intestinal stem cells. We upregulate two separate branches of the Unfolded protein response, ATF6 and XBP1 in colon cancer cell lines and find that, by inhibiting translation, this decreases the growth of cancer cells.
We next explore a genetic model of ER stress, by heterozygous deletion of UPR master regulator Grp78. Grp78 heterozygosity harbors no phenotypical alterations in wildtype intestines, but decreases polyp formation in both Apc and Apc-Kras mutated intestines. Moreover, heterozygosity of Grp78 reduces GLUT1 protein expression and thus reduces glucose uptake, resulting in diminished glycolytic capacity of mutated Kras cells. Lastly, we target mitochondrial ribosomal proteins (MRPs) in an intestinal adenoma model. MRPs are critical for biogenesis of the OXPHOS complex and thus play a role in energy metabolism. However, we show no effect of Mrpl54 heterozygosity on adenoma formation in mice.
These results indicate that ER stress and targets of the UPR can disturb cancer growth via different pathways and provide novel insights in therapeutic strategies in (colorectal) cancer.